Antitumor effect of Melaleuca alternifolia essential oil and its main component terpinen-4-ol in combination with target therapy in melanoma models

Marta Di Martile,Stefania Garzoli,Rino Ragno,Manuela Sabatino,Elisabetta Valentini,Simona D’Aguanno,Donatella Del Bufalo

doi:10.1038/s41420-021-00510-3

Abstract

Essential oils (EOs) have been recently emerging for their promising biological activities in preventing tumorigenesis or progression of different tumor histotypes, including melanoma. In this study, we investigated the antitumor activity of a panel of EOs in different tumor models. The ability of Melaleuca alternifolia (tea tree oil) and its main component, terpinen-4-ol, to sensitize the target therapy currently used for melanoma treatment was also assessed. Our results demonstrated that EOs differently affect the viability of human cancer cells and led us to select six EOs effective in melanoma and lung cancer cells, without toxic effects in human fibroblasts. When combined with dabrafenib and/or trametinib, Melaleuca alternifolia synergistically reduced the viability of melanoma cells by activating apoptosis. Through machine learning classification modeling, α-terpineol, tepinolene, and terpinen-4-ol, three components of Melaleuca alternifolia, were identified as the most likely relevant components responsible for the EO’s antitumor effect. Among them, terpinen-4-ol was recognized as the Melaleuca alternifolia component responsible for its antitumor and proapoptotic activity. Overall, our study holds promise for further analysis of EOs as new anticancer agents and supports the rationale for their use to improve target therapy response in melanoma.

Highlights

Cutaneous melanoma is the most aggressive type of skin cancer
A panel of essential oils (EOs) differently affects the viability of melanoma cells The antitumor activity of 61 EOs (Table S1) was firstly assessed for their ability to affect the proliferation/viability of M14 melanoma cell line (50 μg/ml, 72 h)
We determined the ability of TTO to synergize with target therapy in melanoma models

Summary

Introduction

Cutaneous melanoma is the most aggressive type of skin cancer. BRAF represents the most common driver mutation present in ~50% of patients and predicting a more aggressive behavior[1]. Target therapy and immunotherapy represent a great opportunity for melanoma treatment, patients often face lack of clinical response, the emergence of resistance to treatment, and invalidating side effects[2]. Compounds extracted from plants have demonstrated their effectiveness in different diseases, including melanoma[3]. Scientific evidences have demonstrated that, among natural compounds, essential oils (EOs) showed great potential for the management of a number of diseases including cardiovascular[8], diabetes[9], and Alzheimer[10]. EOs represent a valid source to prevent the invasion of SARS-CoV-2 into the human body[11], or to downregulate angiotensinconverting enzyme 2 expression in epithelial cells[12]

Methods

Results

Conclusion